ph ii trial of carboplatin and pemetrexed with or without azd1775 for untreated lung cancer

Conditions: Previously Untreated Stage IV Non-Squamous Non Small Cell Lung Cancer

Summary: the aim of this study is to combine azd1775 with standard front-line chemotherapy in subjects with advanced nsclc.

this is a randomised, phase ii trial comparing azd1775 plus pemetrexed and carboplatin followed by maintenance azd1775 and pemetrexed versus pemetrexed and carboplatin followed by maintenance pemetrexed in patients with previously untreated metastatic non-squamous nsclc with tp53 mutations. the primary endpoint of the trial is assessment of progression-free survival (pfs).

Eligibility criteria:
inclusion criteria * provision of informed consent prior to any study specific procedures * histologic or cytologic diagnosis of advanced nsclc, recurrent or stage iv disease (according to american joint committee on cancer (ajcc) staging system, v7.0). * no prior chemotherapy for locally advanced or metastatic disease * subjects with a known egfr mutation must have received previous treatment with an egfr tyrosine kinase inhibitor; and subjects with a known alk translocation must have received previous treatment with an alk inhibitor. * no prior radiation therapy to the whole pelvis or to ≥25% of the total bone marrow area. * at least one measurable lesion according to response evaluation criteria in solid tumours (recist) v1.1 * mandatory availability of tumour tissue (archival or fresh if archival is not available) for tp53 determination. * eastern cooperative oncology group (ecog) performance status (ps) score of 0 or 1. * absolute neutrophil count (anc) ≥1500/μl * hemoglobin (hgb) ≥10 g/dl * platelets ≥100,000/μl * alanine aminotransferase (alt) and aspartate aminotransferase (ast), ≤3.0 x the upper limit of normal (uln); 5 x uln if known hepatic metastases * total bilirubin ≤1.5 x uln, unless secondary to gilbert's disease * serum creatinine ≤1.5 x uln and a calculate creatinine clearance (crcl) ≥45 ml/min by the cockcroft-gault method * ability to swallow oral medication * fertile male subjects willing to use at least one medically acceptable form of birth control for the duration of the study and for 2 weeks after treatment stops * female subjects who are not of childbearing potential and fertile female subjects of childbearing potential who agree to use adequate contraceptive measures who are not breastfeeding, and who have a negative serum or urine pregnancy test within 72 hours prior to start of study treatment * predicted life expectancy ≥12 weeks * must be ≥18 years of age * willingness and ability to comply with study and follow-up procedures * ability to understand the nature of this trial and give written informed consent exclusion criteria * use of a study drug ≤21 days or 5 half-lives (whichever is shorter) prior to the first dose of azd1775 * major surgical procedures ≤28 days of beginning azd1775, or minor surgical procedures ≤7 days * known central nervous system (cns) disease * subject has had prescription or non-prescription drugs or other products (i.e. grapefruit juice) known to be sensitive cyp3a4 substrates * any known hypersensitivity or contraindication to the components of study treatment * any of the following cardiac diseases currently or within the last 6 months as defined by new york heart association (\[nyha\] appendix g) ≥ class 2 * corrected qt interval (qtc) \>470 msec (as calculated by fridericia correction formula) at study entry or congenital long qt syndrome. * pregnant or lactating * any serious, active underlying medical condition that would impair the ability of the subjects to receive study treatment * unable or unwilling to take folic acid or vitamin b12 * presence of other active cancers, or history of treatment for invasive cancer ≤3 years * psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol

Keywords: stage iv lung cancer